Process for preparation of alpha-hydroxy-beta, beta-dimethyl-gamma-hydroxy butyric acid or gamma-lactone



Patented Dec. 15, 1942 PROCESS FOR PREPARATIONDROXY-flB-DMETHYL-q-HYDROXY BU- TYRIC ACID OR 'Y-LACTONE Herbert Carter,Urbana, 111., assignor to Abbott Laboratories, North Chicago, 111., acorporation of Illinois No Drawing. Application January 2, 1941, SerialNo. 372,906

6 Claims.

The present invention is directed to an improved process for preparinga-hydroxy-p,3-dimethyl-'y-hydroxy butyric acid or its corresponding'y-butyrolactone.

The substituted butyric acid or lactone of the present invention is ofparticular value as an intermediate and is of special interest at thepresent time because of its use in the synthesis of the therapeuticpantothenic acid. Previously proposed processes for preparing the acidor lactone intermediate have been found inefiicient and generallycommercially unsatisfactory.

The principal object of the present invention is to provide the art withan efiicient and practical process for preparingu-hydroxy-s,p-dimethyl-'y-hydroxy butyric acid or its 'y-lactone.

Other objects will be apparent as the description hereinafter proceeds.

I have discovered an improved process for preparing the desiredintermediate which comprises generally the use of crudea-methylolisobutyraldehyde, the formation of the cyanohydrin orbutyronitrile reaction product, followed by the hydrolysis of thereaction product. I have also discovered that this process is free fromthe disadvantages of prior processes and that this the process of thepresent invention gives excellent yields of a commercially satisfactoryproduct.

The following detailed example will serve to illustrate a preferredprocess of the present invention.

Example isobutyraldehyde-formalin-potassium carbonate reaction mixture)is first dissolved in about 1 liter of water warmed to about 60'70 C.and the resulting solution cooled. A second solution is next prepared bydissolving about 133 grams of calcium chloride in 500 c. c. of water,cooling well and then adding thereto about 98 grams of potassiumcyanide. The calcium chloride-potassium cyanide solution is then addedat once to the cooled a-methylolisobutyraldehyde solution and nitrogengas bubbled through the resulting reaction mixture for a few minutes.

The alkaline reaction mixture containing the butyronitrile intermediateis next allowed to stand, e. g. in a stoppered fiask at a temperature ofabout -45 C. for about 15-18 hours. After standing, the reactionsolution is then heated on a steam cone to '70-80 0., about l51.grams ofoxalic acid (dihydrate) are added, and the mixture shaken for a fewminutes. The calcium oxalate formed is filtered off, about 5 c. c. ofconcentrated hydrochloric acid is added and the solution concentrated toa gum on a water pump in accordance with the usual practice.

The gummy residue is then extracted with dry acetone, the potassiumchloride filtered off, an equal volume of dry benzene added and thesolution again concentrated to a gum. The residue is once again taken upin dry acetone, filtered, if necessary, and the acetone distilled on thewater pump. Fractional distillation of the residue yields the purelactone derivative distilling at about -130 C. at 18 mm. pressure.

The distilled product obtained by the above process is in the lactoneform and contains the usual anhydro-ring. If the acid form is desired,it may be obtained directly from the reaction solution by separation ofthe hydrolyzed product from the reaction mixture.

It will be understood that the present invention is not limited to theabove example. In place of potassium cyanide, for example, other alkalimetal cyanides may be used while in place of calcium chloride otheralkaline earth metal' tion product as described in the example 'are Imerely illustrative and that the present invention is not limitedthereto. Other well known purification procedures or variousmodifications of the described procedure, for example, may be used asdesired.

It will be obvious to those skilled in the art that the presentinvention is not limited to the illustrated example. Variousmodifications of the process falling within the scope of the presentinvention are intended to be covered by the following claims.

I claim:

1. In the process of preparing compounds selected from the groupconsisting of a-hydroxyp, fi-dimethyl-' -hydroxy-butyric acid and itscorresponding 'y-lactone, the step which consists in reacting in aqueoussolution methylolisobutyraldehyde with an alkali metal cyanide in thepresence of an alkaline earth metal halide to form the cyanohydrinreaction product.

2. In the process of preparing compounds selected from the groupconsisting of a-hydroxyfl, p-dimet'nyl -hydroxy-butyric acid and itscorresponding v-lactone, the step which consists in preparing-hydroxy-p, p-dimethyl-v-hydroxy-butyronitrile by reactinga-methylolisobutyraldehyde with alkali metal cyanide in the presence ofcalcium chloride in aqueous solution.

3. In the process of preparing compounds selected from the groupconsisting of a-hydroxyp, p-dimethyl-- -hydroxy-butyric acid and itscorresponding -lactone, the steps which consist in reacting in aqueoussolution u-methylolisobutyraldehyde with an alkali metal cyanide in thepresence of an alkaline earth metal halide to form the cyanohydrinreaction product, and then hydrolyzing the cyanohydrin product in thealkaline reaction mixture at a temperature of about 30-100 C.

4. In the process of preparing compounds selected from the groupconsisting of a-hYdIOXY- p, p-dimethyl-' -hydroxy-butyric acid and itscorresponding 'y-lactone, the steps which consist in preparinga-hydroxy-B, c-dimethyl-v-hydroxt butyronitrile by reactinga-methylolisobutyraldehyde with alkali metal cyanide in the presence ofcalcium chloride in aqueous solution, and then hydrolyzing the resultingbutyronitrile product in the alkaline reaction mixture at a temperatureof about -45 C.

5. In the process of preparing compounds selected from the groupconsisting of a-hydroxyp, B-dimethyl-' -hydroxy-butyric acid and itscorresponding 'y-lactone, the steps which comprise reacting in anaqueous solution a-methylolisobutyraldehyde with an alkali metal cyanidein the presence of an alkaline earth metal halide to form thecyanohydrin reaction product, hydrolyzing the cyanohydrin product in analkaline reaction mixture at a temperature substantially below theboiling point of said mixture, and then separating the butyric acidcompound from the reaction mixture.

6. In the process of preparing a-hydroxy-p, p-dimethyl- -butyrolactone,the steps which comprise preparing a-hydroxy-fi,fl-dimethylwhydroxy-butyronitrile by reacting crudemethylolisobutyraldehyde with potassium cyanide in the presence ofcalcium chloride in aqueous solution, hydrolyzing the butyronitrileproduct in the alkaline reaction mixture at a temperature of about 3045C., separating the hydrolyzed product from the reaction mixture andvfractional distilling the resulting product to obtain the desired-lactone in substantially pure form.

HERBERT E. CARTER.

